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Background  Primary distal renal tubular acidosis (dRTA) caused by mutations in the genes that codify for the H + −ATPase pump subunits is a heterogeneous disease with a poor phenotype-genotype correlation. Up to now, large cohorts of dRTA Tunisian patients have not been analyzed, and molecular defects may differ from those described in other ethnicities. We aim to identify molecular defects present in the  ATP6V1B1 ,  ATP6V0A4  and  SLC4A1  genes in a Tunisian cohort, according to the following algorithm: first,  ATP6V1B1  gene analysis in dRTA patients with sensorineural hearing loss (SNHL) or unknown hearing status. Afterwards,  ATP6V0A4  gene study in dRTA patients with normal hearing, and in those without any structural mutation in the  ATP6V1B1  gene despite presenting SNHL. Finally, analysis of the  SLC4A1  gene in those patients with a negative result for the previous studies.    Methods  25 children (19 boys) with dRTA from 20 families of Tunisian origin were studied. DNAs were extracted by the standard phenol/chloroform method. Molecular analysis was performed by PCR amplification and direct sequencing.    Results  In the index cases,  ATP6V1B1  gene screening resulted in a mutation detection rate of 81.25%, which increased up to 95% after  ATP6V0A4  gene analysis. Three  ATP6V1B1  mutations were observed: one frameshift mutation (c.1155dupC; p.Ile386fs), in exon 12; a G to C single nucleotide substitution, on the acceptor splicing site (c.175-1G > C; p.?) in intron 2, and one novel missense mutation (c.1102G > A; p.Glu368Lys), in exon 11. We also report four mutations in the  ATP6V0A4  gene: one single nucleotide deletion in exon 13 (c.1221delG; p.Met408Cysfs*10); the nonsense c.16C > T; p.Arg6*, in exon 3; and the missense changes c.1739 T > C; p.Met580Thr, in exon 17 and c.2035G > T; p.Asp679Tyr, in exon 19.    Conclusion  Molecular diagnosis of  ATP6V1B1  and  ATP6V0A4  genes was performed in a large Tunisian cohort with dRTA. We identified three different  ATP6V1B1  and four different  ATP6V0A4  mutations in 25 Tunisian children. One of them, c.1102G > A; p.Glu368Lys in the  ATP6V1B1  gene, had not previously been described. Among deaf since childhood patients, 75% had the  ATP6V1B1  gene c.1155dupC mutation in homozygosis. Based on the results, we propose a new diagnostic strategy to facilitate the genetic testing in North Africans with dRTA and SNHL.

bmc medical genetics

Molecular diagnosis of distal renal tubular acidosis in Tunisian patients: proposed algorithm for Northern Africa populations for the ATP6V1B1, ATP6V0A4 and SCL4A1genes